Forces, Kinetics, and the Thermodynamics of Crowded Cell Surfaces

The mammalian cell membrane is covered with a protective “shield” of proteins and sugars that enables cells to interact with their local environment. Important cell functions mediated by the cell membrane, like the delivery of growth factors and antibodies to cell surface receptors, requires these soluble species to penetrate through and interact within this thick shield that covers and protects the cell surface. The goal of this project is to develop a fundamental understanding of the physical organization of the proteins and sugars that make up the shield, and to identify the mechanisms of molecular transport and binding on the cell membrane. This will be achieved by studying the binding of one particular soluble species, a monoclonal antibody, on both live cells and on engineered synthetic surfaces. In addition to advancing a basic biophysical understanding of the cell membrane, this project may have significant broader impacts in biopharmaceutical drug discovery of antibody therapeutics that target diseased cell surfaces. The investigator’s research group will broaden STEM participation by integrating the proposed research with a two-part outreach program. First, the group will engage underrepresented groups with academic research, targeting junior transfer students to ease their transition to a four-year university and broaden their professional development. Second, the PI will teach effective science communication skills to students, which is an important skill that is largely missing in the traditional STEM curriculum. The objective of this project is to determine how the molecular organization of the cell surface glycocalyx modulates the biophysical interactions of proteins, polysaccharides, and macromolecules on the cell membrane. The project will combine coarse-grained molecular dynamics simulations, in-vitro reconstitution of engineered cell surfaces, and live cell experiments to provide a spatial and temporal description of the molecular-to-mesoscale surface interactions that govern plasma membrane organization. By quantifying the transport and binding of monoclonal antibodies to engineered antigen receptors with various chemical and physical properties, the project will determine the cooperative dynamics of multibody surface protein interactions. The project seeks to advance a quantitative framework to isolate the effects of protein glycosylation, density, charge, stiffness, and other biophysical properties on live plasma membranes. This project will determine surface protein interactions that cannot be obtained from studying purified proteins in isolation. Through the development of new tools and concepts, this project will advance the fundamental understanding of the cell membrane dynamics that govern a variety of surface-mediated cellular processes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.